Antiviral Agents

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Interferons - interferon alfa-2b (Intron A)

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1. AGENT:
-interferon alfa-2b: recombinant, purified IFN
- PEG-IFN: pegylated interferon. increased half life v. interferon alfa-2b

2. TARGET:
- hepatocytes infected by HBV and HCV. only chronic conditions

3. MECHANISM:
- bind to specific cell receptors
- induce intracellular events (enhance macrophage phagocytic activity, increase lymphocyte cytotoxicity, inhibit virus replication)

4. TX:
- used in conjunction with ribavirin.
- chronic hep. C (24-48wks)
- pegylated interferon alfa-2b of 2a (PEG-intron or Pegasys) are preferred. used once/wk

5. ADVERSE:
- flu-like, fatigue, peripheral neuropathy
- bone marrow suppression (anemia, leukopenia, thrombocytopenia)
- neuropsychiatric symptoms

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Ribavirin

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- guanosine analouge, used in combination therapy with interferons
- doubles sustained viral responses but increases side effects
- reversible hemolysis, anemia, high risk of congenital defects (must be given with two-line contraception therapy)

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Antiherpes Nuceloside analogs

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1. Acyclovir: guanine nucleoside analog. active against HSV-1, HSV-2, VZV, EBV

2. Valaciclovir: prodrug of acyclovir. higher absorption as prodrug. cleaved in GI

3. Famciclovir: prodrug of penciclovir, with similar properties to acyclovir. much longer half life than acyclovir

4. Ganciclovir: similar to acyclovir, but with different properties. active against CMV, HSV, VZV

5. Valganciclovir: prodrug of ganciclovir. much improved oral bioavailabilty. (~ to IV)

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Acyclovir

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1. TARGET: virus-encoded DNA polymerase

2. MECHANISM: inhibits viral DNA synthesis
- first phosphorylation: viral thymidine kinase (selective for HSV infected cells)
- second and third phosphorylation: cellular phosphates
- then can act as competitive inhibitor of HSV DNA polymerase

3. TX: HSV-1, HSV-2, VZV

4. ADVERSE:
- acute renal failure secondary to crystal deposition in tubules (hydrate pt), neurological toxicities
- ganciclovir will cause bone marrow suppression, neurological toxicity, and abnormal LFTs

5. RESISTANCE:
- viruses with reduced, absent thymidine kinase will be resistant
mutations in UL97 phosophotransferase will lead to ganciclovir resistance
- Foscarnet and cidofovir do not require thymidine kinase. active against HSV and CMV

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M2 inhibitors: amantadine (Symmetrel) and rimantadine

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1. TARGET: M2 protein

2. MECHANISM:
- blocks passage of protons through viral envelope (formed by M2) in endocytozed viral vacuole.
-because pH does not lower, hemagglutinin does not have conformational change, and therefore cannot facilitate fusion of envelope with endosomal wall

3. TX: for influenza A not B. give within 30-48 hours of symptom onset

4. ADVERSE:
- CNS: agitation, anxiety, depression, dizziness
- GI: nausea, anorexia, diarrhea, constipation
- rimantadine has less CNS effect

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Neuraminidase inhibitors- Oseltamivir (Tamiflu) and Zanamivir

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1. MECHANISM:
- inhibits neuraminidase (glycoprotein on viral surface). prevents viral aggregration and release

2. TX:
- oseltamivir (oral) and zanamivir (inhalation) used for influenza A and B

3. ADVERSE
- oseltamivir: GI, HA
- zanamivir: GI, ENT irritation

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Antiretroviral Agents

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1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
- act on catalytic site of RT
- phosphorylated 3 times
- compete with dTTP for incorporation into proviral DNA, leading to chain termination

2. Nucleotide Reverse Transcriptase Inhibitor (NtRTIs):
- catalytic site of RT
- phosphorylated 2 times
- compete with dATP for incorporation into viral DNA

3. Non-Nucleotide Reverse Transcriptase Inhibitors (NNRTI):
- active at allosteric site of RT
- prevents polymerization of viral RNA to DNA

4. Protease inhibitors:
- HIV protease
- active site of protease
- virus cannot undergo proteolytic maturation

5. Fusion inhibitor:
- inhibits gp41
- prevents fusion of HIV with host cell

6. Integrase Inhibitor (II):
- inhibits In
- prevents incorporation of viral DNA into host DNA.

7. CCR5 inhibitor:
- CCR5 receptor on cell surface
- inhibits binding of gp120 to CCR5 co-receptor

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Zidovudine (ZDV or AZT, Retrovir)

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- NRTI
- deoxythymidine analouge
- more active in dividing v. resting cells
- active against HIV-1 and HIV-2

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Tenofovir DF (Viread)

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- NtRTIs
- deoxyadenosine analouge
- active in dividing and resting cells
- active against HIV-1, HIV-2, HBV

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Efavirenz

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-NNRTIs
- active against HIV-1 but not HIV-2

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Lopinavir (Kaletra)

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- PI
- given with ritonavir which inhibits hepatic P450, thereby increasing plasma levels of Lopinavir
- active against HIV-1 and HIV-2

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Enfuvirtide (Fuzeon)

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- FI

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Raltegravir

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- II

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Maraviroc

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- CCR5 inhibitor

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HIV antiretroviral tx indicators

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1. symptomatic- treat

2. asymptomatic
- CD4 < 200 : treat
- CD4 200-350 : treat
- CD4 > 350: tx dependent upon pt. profile

3. Factors influencing tx:
- risk of clinical disease progression
- willingness of pt
- drug toxicity profile and burden
- drug resistance
- drug-drug interactions

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Antiretroviral adverse effects

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1. NRTIs and NtRTIS:
- lactic acidosis, hepatic steatosis, peripheral fat wasting, peripheral neuropathy, nausea
- Zidovudine: bone marrow toxicity and myopathy

2. NNRTIs:
- rash, increased transaminases
- Efavirenz: vivid dreams, hallucinations

3. PI
- GI, lipodystrophy (wasting, fat accumulation, sunken cheeks, and fat deposition on back), hyperlipidemia, DM

4. FI
- Enfuvirtide: injection site rxn, bacterial PNA